Is PKD1 p.Pro765Ser (c.2293C>T) pathogenic?

PKD1 p.Pro765Ser (c.2293C>T) is classified Uncertain significance in PKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0458%, mid); Associated with Inborn genetic diseases.

What condition is associated with PKD1 p.Pro765Ser (c.2293C>T)?

PKD1 p.Pro765Ser (c.2293C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PKD1 p.Pro765Ser (c.2293C>T) in the general population?

PKD1 p.Pro765Ser (c.2293C>T) is ultra-rare (popmax 0.0458%, mid) (gnomAD).

What do computational predictors say about PKD1 p.Pro765Ser (c.2293C>T)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

PKD1 p.Pro765Ser

c.2293C>T · VCV4137465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0458%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.21, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,908 bp · p 6.5e-05 · regional, not allelic
Overall
CADD	9.429	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0458% Middle Eastern · 2/4,370 alleles

Filtering AF 0.0081% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00339%

Overall 0.00131% 20/1,529,648 alleles · ultra-rare exomes 18/1,377,462 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0458%	2,185
Admixed American	0.00196%	50,958
Remaining individualsnot grpmax-eligible	0.00168%	59,642
European (non-Finnish)	0.0014%	71,451

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PKD1
Protein: p.Pro765Ser
Coding: c.2293C>T
MANE Select: NM_001009944
Type: single nucleotide variant
Location: chr16:2114730 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 765: the pkd 2 domain

Full PKD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PKD1 p.Pro765Leu Uncertain significance ★★ ⚠ same residue
PKD1 c.11017-10C>A Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.1385+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.3295+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKD1 p.Arg138Ter Pathogenic ★★ same condition
PKD1 p.Arg4021Ter Pathogenic ★★ same condition
PKD1 p.Gln1172Ter Pathogenic ★★ same condition
PKD1 p.Gln2014Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pkd1-p-pro765ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown